MX2007005690A - Process for the synthesis of rocuronium bromide - Google Patents

Abstract

The invention encompasses processes for synthesizing l-[17β-acetyloxy-3α- hydroxy-2β-(4-morpholmyl)-5α-androstan-16β-yl]-l-(2-propenyl)pyrrolidinium bromide (rocuronium bromide) and intermediates thereof.

Description

PROCESS FOR THE SYNTHESIS OF ROCURONIO BROMIDE Field of the Invention The invention comprises processes for synthesizing 1- [17p-acetyloxy-3a-hydroxy-2p- (4-morpholinyl) -5a-androstan-16p-yl] -1- (2-propenyl) pyrrolidinium bromide (rocuronium bromide) and intermediate of him.

Background of the Invention The bromide of 1- [17β- (acetyloxy) -3a-hydroxy-2p- (4-morpholinyl) -5a-androstan-? ßß- ??] -1- (2-propenyl) pyrrolidinium (rocuronium bromide) of the Formula I, has the following structure: i with a formula of C32H53Br 204 and a molecular weight of 609, 70. Rocuronium bromide is used as a non-depolarizing neuromuscular blocking agent with rapid to intermediate onset according to the dose and an intermediate duration. It acts by competing for the cholinergic receptors on the motor endplate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium.

Rocuronium bromide of formula I is marketed under the name ZEMURON® and is supplied as a sterile, non-pyrogenic, isotonic solution that is clear, colorless to yellow / orange, for intravenous injection only.

The preparation of rocuronium bromide is disclosed in U.S. Patent Nos. 5,817,803 and 4,894,369 and in U.S. Publication No. 2005/0159398.

U.S. Patent No. 4,894,369 ("patent" 369") discloses the preparation of Rocuronium bromide through 2a, 3a-ββ-16β- (1-pyrrolidinyl) -5a-androstan-17p-ol of the formula II: wherein R3 is C, N-CH3 or a direct C-C bond. The performance is modest (around 60% p / p yield). The patent discloses the reaction of 2a, 3a-epoxy-16p- (1-pyrrolidinyl) -3a-androstan-17p-ol with morpholine in the presence of water to give 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) ) -5a-androstan-3a, 17β-diol. The step is carried out for a time of the reaction after days after which the solvents are removed by evaporation and the final product is crystallized from acetone and then by recrystallization from methanol.

Then, 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1 reacts with an acetylation reagent to obtain 2β- (4 -morpholinyl) -16β- (1-pyrrolidinyl) -5oc-androstan-3a-ol,. In this process of acetylation the product is obtained with low yields of 48%, which comprises a process of purifying from the remaining starting diol, and the collateral product diacetate, by means of column chromatography and then by crystallization from a mixture of diethyl ether and n-hexane. See patent? 369, column 5, 11. 31-50 (example 7).

Finally, the mono-quaternary ammonium compound, rocuronium bromide, is prepared by reaction of the monoacetate derivative and a large excess of allyl bromide (8.7 equivalents) in a pressure flask at room temperature for 22 hours. See id. In column 8, 11. 27-46 (example 23). The product is purified by column chromatography on alumina and the combined pure fractions are subsequently crystallized from dichloromethane-diethyl ether to give the pure rocuronium bromide.

US publication No. 2005/0159398 ("publication 398") discloses the preparation of a Rocuronium derivative through a bis-acetylated intermediate. The bis-acetylated compound passes through a selective de-acetylation reaction to give a mono-acetate product, which is further purified by two crystallizations to give the desired product in 52% yields. See publication 398, page 8, 112-115.

Each step of the purification reduces the yield, increases the cost of production and increases the manufacturing time. Therefore, processes that reduce manufacturing cost and time while simultaneously increasing product yield and purity are highly desirable. Processes that simplify the production process are also desired. The process of the present invention faces these drawbacks of prior art.

Extract of the invention An embodiment of the invention comprises compound VI isolated from the following structure: saw Another embodiment of the present invention comprises crystalline compound VI.

Yet another embodiment of the invention comprises a process for increasing the isomeric ratio of Compound VI to Compound Vl-a of the following structure: which comprises combining a starting Compound VI containing 10% to 40% area by HPLC of Compound Vl-a with an organic solvent miscible with water to obtain a suspension; stir the suspension at a temperature of 60 ° C to 80 ° C for a sufficient time to obtain a solution; add water to the solution to form a suspension; and isolating Compound VI from the mixture; wherein the isolated Compound VI contains no more than 3% area by HPLC of Compound Vl-a.

An embodiment of the invention comprises a process for preparing the Rocuronium bromide of the formula I (hereinafter "Roe") preparing Compound VI with less than 10% area by HPLC of Compound Vl-a by the process of the present invention, and converting it to Rocuronium bromide. The invention also comprises a process for preparing Compound IV: which comprises forming a solution of Compound VI with less than 10% of the compound Vl-a, and an organic solvent miscible with water optionally combined with an organic solvent immiscible with water; add at least one reducing agent to the solution at a temperature of -15 ° C to 10 ° C to obtain a mixture; stir the mixture at a temperature of 20 ° C to 24 ° C; and isolating Compound VI from the mixture having a purity of at least 85% area by HPLC.

An embodiment of the present invention comprises a process for preparing Roe of formula I by preparing compound IV having a purity of at least 85% area by HPLC as described above, and converting it to Roe of formula I.

Another embodiment of the invention comprises a process for preparing Compound VII which comprises forming a suspension of Compound IV, morpholine, and at least one acid catalyst; stirring the suspension at a temperature from 100 ° C to the reflux temperature for 24 hours to 48 hours; and isolating Compound VII from the suspension.

Yet another embodiment of the present invention comprises a process for preparing Roe of the formula I by preparing the compound VII described above, and converting it into Roe of the formula I.

An embodiment of the invention comprises a process for preparing Compound VIII comprising Compound VII, a polar organic solvent, and at least one acetylation reagent with at least one base to obtain a mixture, and isolating Compound VIII from the mixture.

Another embodiment of the invention comprises a process for preparing rocuronium bromide comprising a process for preparing rocuronium bromide from compound VIII comprising combining Compound VIII, a polar aprotic organic solvent, allyl bromide, and at least one inorganic base to obtain a mixture; and isolate rocuronium bromide.

The isolated rocuronium bromide can be purified by a process comprising: dissolving the rocuronium bromide isolated in at least one polar aprotic organic solvent to form a solution; adding an optionally combined bleaching agent with a base to the solution to form a first suspension; filter the first suspension; add the resulting filtrate to an antisolvent; shake vigorously to obtain a second suspension; recover wet solid Rocuronium bromide from the second suspension; and drying the Rocuronium bromide at a temperature not higher than 35 ° C.

Still another embodiment of the present invention comprises a process for the preparation of the quaternary ammonium salt, Roe, of the formula I which comprises combining a starting Compound VI containing 10% to 40% area by HPLC of compound VI-a with an organic solvent miscible with water to obtain a suspension; stir the suspension at a temperature of 60 ° C to 80 ° C to obtain a solution; form a suspension by adding water to the solution; isolating Compound VI from the suspension, wherein Compound VI is less than 3% area by HPLC of Compound VI-a; forming a solution of Compound VI with less than 3% of the compound Vl-a, and at least one organic solvent miscible with water; add at least one reducing agent to the solution at a temperature of -15 ° C to 10 ° C to obtain a mixture; stir the mixture at a temperature of 20 ° C to 24 ° C; isolating Compound VI from the mixture having a purity of 85% by HPLC, preferably 90%; forming a suspension of Compound IV, morpholine, and at least one acid catalyst; stirring the suspension at a temperature of 100 ° C at reflux temperature for at least 24 hours to 48 hours; isolating Compound VII from the suspension; combining Compound VII, a polar organic solvent, and at least one acetylating reagent with at least one base to obtain a mixture; isolating Compound VIII from the mixture; combining Compound VIII, a polar aprotic organic solvent, allyl bromide, and at least one inorganic base to obtain a mixture; and isolate rocuronium bromide.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the X-ray diffraction pattern of the 2α-epoxy- [beta] - (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Figure 2 illustrates the DSC curve for 2a, 3a-γ-16β- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Figure 3 illustrates the TGA curve of 2a, 3a-epoxy-16P ~ (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Figure 4 illustrates the spectrum of | "| H-NMR of 2a, 3a-epoxy-16p- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Figure 5 illustrates the 13 C-NMR spectrum of 2a, 3a-epoxy-16 - (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Figure 6 illustrates the MS spectrum of 2a, 3a-ββ-16β- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Figure 7 illustrates the IR spectrum of 2a, 3a-γ-16β- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI.

Detailed description of the invention The invention comprises compound VI isolated from the following structure.

The isolated compound of formula VI can be characterized by data selected from: a spectrum of 13 C-NMR having chemical carbon shifts at 218.3, 69, 53.9, 52.2, 51.9, 50.8, 47 , 5, 46.9, 38.1, 36.2, 34.4, 33.8, 31.9, 30.6, 28.9, 28, 26, 6, 23.2, 20, 23, 9 and 12.9 ppm a spectrum of 13 C-NMR which is substantially illustrated in Figure 5; a spectrum of 1H-NMR having chemical shifts of hydrogen at 3.17-3.09, 2.92, 2.79, 2.64, 2.1, 1.95-0.66, 0.9 and 0 75 ppm; an "H" NMR spectrum that is substantially illustrated in Figure 4, a mass spectrum (FAB (+), m / z) having a peak of MH + at 358.2, a mass spectrum illustrated substantially in Figure 7, an IR spectrum having peaks at 1736, 3452 and 1157 cm-1 and an IR spectrum that is substantially illustrated in Figure 8.

The invention also comprises crystalline compound VI. The crystalline compound VI can be characterized by powder X-ray diffraction peaks at 10.3, 14.8, 17.5, 18.4 and 19 degrees two theta, ± 0.1 degrees two theta. The crystalline compound VI can also be characterized by data selected from a group consisting of powder X-ray diffraction peaks at 10, 9, 20.7, 22, 24.1, 25, 9 and 27 degrees two theta, ± 0, 1 degrees two theta; a powder X-ray diffraction illustrated in Figure 1; a weight loss of 0.2% by weight, determined by the TGA analysis; a TGA curve that is substantially illustrated in Figure 3; a DSC having an endothermic peak at 146 ° C; a DSC curve illustrated substantially in Figure 2 and by a melting point of 155 ° C.

The invention also comprises processes for the synthesis of rocuronium bromide using a process that increases the yields while reducing the impurity profile of the intermediates and the final product. Partly, the impurities are reduced when 2 equivalents of moles of pyrrolidine are allowed to react with Compound V, defined below, to avoid the production of unwanted by-products and / or unnecessary purification steps during the synthesis of the intermediate. In addition, the recovery of the product is much easier which results in a product that contains only a small amount of by-products, such as the compounds of Formula Vl-a and / or VI-c: Vl-a Vf-c As used herein, the term "base" refers to a substance that accepts one or more protons during a chemical reaction. The term "strong base" refers to a substance having a high affinity to H + including, but not limited to, NaOH, NaHCO 3, Na 2 CO 3, KOH, KHCO 3, or K 2 CO 3.

As used herein, the term "wet solvent" refers to a solvent that contains a volume of 1% to 7% water in the total volume of the solvent.

The process for the preparation of Compound VI which comprises combining 2a, 3a-epoxy-5a ~ androstan-16p-ol-17-one, Compound V, and pyrrolidine in an organic solvent miscible with water at a temperature of 40 ° C at the reflux temperature to obtain a mixture; stirring the mixture at a temperature of 40 ° C to reflux temperature for 30 minutes to one hour to obtain Compound VI; and isolating Compound VI.

Compound V can be prepared by reacting a solution of 2a, 3a, 16a, 17a-bisepoxy-5a-androstan-17p-acetate (Compound III) with an aqueous solution of a strong base in an organic solvent miscible with water at a temperature of 40 ° C at reflux. The organic solvent miscible with water can be any of those described below for the synthesis of Compound VI. However, the most preferred water-miscible organic solvent is methanol and the most preferred base is NaOH.

Alternatively, Compound V can be made in situ prior to the reaction with pyrrolidine. Therefore, the reaction described above can be performed sequentially wherein the 2a, 3a, 16a, 17a-bisepoxy-5a-androstan-17p-acetate (Compound III) is allowed to react with an aqueous solution of a strong base to give Compound V, which is then allowed to react with pyrrolidine to give Compound VI. Therefore Compound V is made without intermediate isolation prior to the synthesis of Compound VI.

Compound III can be obtained, for example, according to the process disclosed by Buckett, W.R. "Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments", J.Med. Chem., 1973, 16 (10), pp. 1116-1124.

Preferably, the organic solvent miscible with water is at least one straight or branched C1-C5 alcohol. Preferably, the Ci-C5 alcohol is a Ci-C3 alcohol. A preferred C1-C3 alcohol is methanol, ethanol or 2-propanol. More preferably, the Ci-C alcohol is methanol.

Preferably, the combination of 2oc, 3a-epoxy-5a-androstan-16p-ol-17-one, Compound V, and pyrrolidine in an organic solvent miscible with water is carried out at a temperature of 40 ° C to 65 ° C, more preferentially from 60 ° C to 65 ° C.

The pyrrolidine must be present in an amount sufficient to give Compound VI without giving large amounts of Compound VI-c. Preferably, the pyrrolidine is present in an amount of 2 or less equivalent moles for each mole equivalent of Compound III.

Preferably, the mixture is stirred at a temperature of 40 ° C to 65 ° C, more preferably 60 ° C to 65 ° C.

Preferably, the mixture is stirred for 30 to 120 minutes. Compound VI can be recovered by any method known to the person skilled in the art. These methods include, for example, adding ice-water to the mixture and filtering the precipitated product.

The reaction of 2oc, 3a-epoxy-5a-androstan-16p-ol-17-one, Compound V, and pyrrolidine generally produces a mixture of isomers Compound VI and Compound Vl-a: saw VI-a The invention also comprises a process for increasing the isomeric ratio of Compound VI to Compound Vl-a which comprises combining a starting Compound VI containing 10% to 40% area by HPLC of Compound VI-a with a organic solvent miscible with water to obtain a suspension; stir the suspension at a temperature of 60 ° C to 80 ° C for a sufficient amount of time to obtain a solution; and isolating Compound VI from the mixture; wherein the isolated Compound VI contains no more than 3% area by HPLC of Compound Vl-a.

Generally, starting Compound VI can contain from 10% to 40% area by HPLC of Compound Vl-a. Preferably, starting Compound VI contains 15% to 30% area by HPLC of Compound Vl-a. More preferably, the starting Compound VI contains 10% to 20% area by HPLC of Compound Vl-a, more preferably the isolated compound of the formula VI contains from 12% to 18% area by HPLC of the compound of the formula Vl-a.

Preferably, isolated Compound VI contains less than 3% area by HPLC of compound Vl-a, more preferably, less than 2% area by HPLC, more preferably less than 1% area by HPLC.

Preferably, the organic solvent miscible with water is at least one Ci_ alcohol, more preferably, methanol, ethanol, propanol, isopropanol or butanol. Preferably, the C1-4 alcohol is methanol.

Preferably, the suspension is stirred at a temperature of 50 ° C to 70 ° C.

Preferably, the water is added dropwise, more preferably, over a period of 90 minutes.

Preferably, the water is added while maintaining the mixture at a temperature of 60 ° C.

Preferably, the water is added in an amount of 3 to 4 volumes of the volume of the organic solvent miscible with water, more preferably 3 volumes of the volume of the organic solvent miscible with water.

Preferably, compound VI containing less than 3% area by HPLC of compound Vl-a can be isolated by cooling the mixture formed after adding water, at a temperature of 5 ° C to 0 ° C, and then filtering and drying. Preferably, the mixture is cooled for a period of 40 to 50 minutes.

The invention also comprises a process for preparing Rocuronium bromide of the formula I i preparing Compound VI with less than 3% area by HPLC of Compound Vl-a as described above, and converting it to Rocuronium bromide.

The invention also comprises a process for preparing Compound IV: which comprises forming a solution of Compound VI with less than 3% of the compound Vl-a and an organic solvent miscible with water optionally combined with an organic solvent miscible with water; add at least one reducing agent to the solution at a temperature of -15 ° C to 10 ° C to obtain a mixture; stir the mixture at a temperature of 20 ° C to 24 ° C; and isolating Compound IV from the mixture having a purity of 85% area by HPLC, preferably at least 90% area by HPLC. Optionally, Compound IV can be obtained with a purity of 97% area by HPLC by dissolving Compound IV isolated in methanol, adding water to promote crystallization and collecting the crystals.

As illustrated in comparative example 27 below, when the process for preparing compound IV disclosed in US Pat. No. 4,894,369 is executed, two major polar impurities are formed. These impurities were identified after the reduction after reduction of the carbonyl group, by NMR, MS and by XRD analysis, which were isomers of the monoepoxide of the desired formula IV. The isomer 2a, 3-epoxy-16a- (1-pyrrolidinyl) -17p-hydroxy-5a-androstane of the formula IV-a (designated compound IV-a) which is obtained with 12% area by HPLC, and the second isomer 2a, 3a-epoxy-16a- (1-pyrrolidinyl) -17a-hydroxy-5a-androstane of the formula IV-b (called compound Vl-b) which is obtained with 5% area by HPLC. In addition, impurity IV-c (dipyrrolidino analog of the following formula) is obtained with no more than 4% area by HPLC.

In addition, the process disclosed in U.S. Patent No. 4,894,369 results in a product with moderate yields of 57% by weight. However, compound IV is obtained by the process of the present invention with a much better yield of 80%.

Compound IV is obtained from the above process with a purity of 85% to 100% area by HPLC, more preferably, from 90% to 100% area by HPLC, more preferably from 97% to 100% area by HPLC.

In addition, the compound IV prepared by the preceding process contains an impurity selected from the group consisting of: the compound IV-a, the compound IV-b, IV-c and mixtures thereof. Preferably, the compound IV-a is present in an amount of less than 2% area by HPLC, more preferably, from 1% to 2% area by HPLC. Preferably, the compound IV-b is present in an amount of less than 1% area by HP1C. In addition, compound IV having less than 2%, preferably less than 0.5% area is obtained by HPLC of compound IV-c of the following formula IV-c Preferably, the compound VI used as a starting material is less than 3% area by HPLC of Compound Vl-a, therefore the obtained compound IV contains less than 2% area by HPLC, more preferably, from the 1% to 2% area by HPLC of compound IV-a, less than 1% area by HPLC of compound IV-b, and less than 2%, preferably less than 0.5% of compound VI-c.

Preferably, the organic solvent miscible with water is at least one C1-5 alcohol. Preferably, the straight or branched C1-.5 alcohol is a C1-3 alcohol. More preferably, the straight or branched Ci_3 alcohol is methanol, ethanol or isopropanol. The most preferred C1-3 alcohol is methanol. When the organic solvent miscible with water is present in combination with an organic solvent immiscible with water, an organic solvent miscible with water is methanol and an organic solvent immiscible with water is methylene chloride.

Preferably, the reducing agent is added at a temperature of 0 ° C to -5 ° C.

The reducing agent used in the reaction is any reducing agent capable of reducing the onyl. The reducing agent is preferably a metal hydride complex, more preferably an alkali metal hydride complex, more preferably, sodium borohydride, potassium borohydride, or sodium trimethoxy borohydride, and even more preferably, sodium borohydride.

Compound IV can be isolated by any method known to the person skilled in the art. These methods include, but not limited to, the concentration under vacuum and optionally the addition of water to the organic phase.

Compound IV can optionally be purified by a process comprising: dissolving Compound IV in an organic solvent; extract the solution at least once with a mineral acid; heat the solution to reflux to distill 2/3 of the solvent; adding water to the solution at a temperature above room temperature to form a suspension; cooling the suspension to induce the precipitation of a solid; recover the solid from the suspension; and drying the solid to obtain Compound IV.

The invention comprises a process for preparing Roe of formula I by preparing compound IV having a purity of at least 90% area by HPLC as described above, preferably more than 95%, and converting it into Roe of formula I .

The invention also comprises a process for preparing Compound VII which comprises forming a suspension of Compound IV, morpholine, and at least one acid catalyst; stirring the suspension at a temperature of 100 ° C under reflux for 24 hours at 48 hours; and isolating Compound VII from the suspension.

The isolation of Compound VII disclosed in U.S. Patent No. 4,894,369, consists in the evaporation of morpholine, which is very inconvenient and time consuming. In addition, the solution of Compound VII also requires the crystallization processes t and recrystallization, thereby reducing the yield and increasing the production cost. See patent? 369, column 4, line 47 to column 5, line 2 (examples 3 and 4). In contrast, the crude compound VII of the present invention is obtained with high molar yields, preferably from 82% to 96%, by the preceding process thus avoiding the processing steps. Moreover, the compound VII obtained by the process of the invention has a purity of 77% to 98% by HPLC, more preferably, from 94% to 98% by HPLC, and can therefore be used in the step next without further purification.

Preferably, the morpholine is in the form of an aqueous solution.

The acid catalyst must be a compound capable of increasing the reaction rate. Typical acidic catalysts include, but are not limited to, mineral acids, organic acids or Lewis acids. A preferred organic acid is p-toluene sulfonic acid, methane sulphonic acid, trichloroacetic acid, or trifluoroacetic acid. Preferably, the mineral acid is sulfuric acid or hydrochloric acid. A preferred Lewis acid is A1C13, ZnCl2, BF3, SnCl4, TiCl4, AgC104, Zn (OAc) 2, or FeCl3. A more preferred Lewis acid is zinc acetate or ferric chloride. The most preferred catalyst is p-toluene sulfonic acid.

Preferably, the suspension is stirred at a temperature of 100 ° C to 110 ° C.

Preferably, the suspension is stirred at a temperature of 100 ° C to 110 ° C to obtain a solution.

Preferably, the solution is maintained for 20 to 50 hours, more preferably under agitation.

Optionally, to increase the speed of the reaction, the suspension can be maintained under pressure, preferably the vapor pressure of the solvent. The pressure is preferably from 0.5 to 1 Kg / cm2. When the suspension is kept under pressure, the temperature of the reaction increases to a temperature of 113 ° C to 117 ° C.

Preferably, compound VII can be isolated by precipitation from a cold dilute aqueous basic solution and drying in a vacuum oven, thus avoiding the passage of the crystallization disclosed in U.S. Patent No. 4,894,369. More preferably, the basic solution is of an alkaline base selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide. The most preferred base is sodium carbonate.

The process for the preparation of compound VII, more preferably, of compound IV, can be carried out on an industrial scale.

The present invention also comprises a process for preparing Roe of the formula I by preparing the compound VII described above, and converting it to Roe of the formula I. As illustrated in comparative example 26 below, the repetition of the process disclosed in US Pat. No. 4,894,369, provides compound VIII with a purity of 81.56% area by HPLC, containing the starting diol, compound VII, in an amount of 5.16% area by HPLC and the diacetate impurity, compound IX, in an amount of 11.93% area by HPLC.

However, the process of the present invention applies the use of a small amount of a base and anhydride as the acetylation reagent and therefore, derives chemoselectively in compound VIII in better yields and with a purity of 90% at 99% area by HPLC before purification. After purification by simple crystallization, the product is obtained with a total yield of 70% and a purity of 97% to 99% area by HPLC, more preferably 99% area by HPLC, without the need to purify chromatography of column.

The invention comprises a process for the preparation of Compound VIII which comprises mixing Compound VII, a polar organic solvent, and at least one acetylating reagent with at least one base to obtain a mixture; and isolating Compound VIII from the mixture.

Compound VII can be obtained by the process of the present invention or by another process, such as disclosed in U.S. Patent No. 4,894,369, incorporated herein by reference.

The polar aprotic organic solvent includes, but is not limited to, ketones, esters, ethers, amides, nitromethane, or halogenated hydrocarbons. A preferred ketone is a C3-6 ketone. A preferred C3_6 ketone is acetone or methyl isobutyl ketone. Preferably, the ester is an ester of C4_6. A preferred C-6 ester is ethyl acetate or isobutyl acetate. A preferred ether is a C3-4 cyclic ether, more preferably, tetrahydrofuran (THF). A preferred amide is a C3-4 amide, more preferably, N, N-dimethylformamide. Preferably, the halogenated hydrocarbon is halogenated hydrocarbon of x-2. A C1-2 halogenated hydrocarbon is dichloromethane or dichloroethane. The most preferred polar aprotic organic solvent is dichloromethane.

The acetylation reagent includes, but is not limited to, acetyl halides, halogenated esters, anhydrides, or esters. A preferred acetyl halide is acetyl chloride. A preferred halogenated ester is ACOCH2CCI3, or ACOCH2CF3. Preferably, the anhydride can be mixed anhydrides or acetic anhydride. Preferably, the ester is isopropenyl acetate. The most preferred acetylation reagent is acetyl chloride or acetic anhydride.

Generally, the base includes an organic base or inorganic base. Organic bases include, but are not limited to, aliphatic amines and aromatic amines. Preferably, the aliphatic amine is triethylamine, diethylisopropylamine, tri-n-propylamine or tributylamine. Preferably, the aromatic amine is 4-dimethylaminopyridine. Inorganic bases include, but are not limited to, alkaline and aluminum bases. Preferably, the alkaline base is sodium carbonate or sodium bicarbonate. A preferred aluminum base is aluminum oxide.

The most preferred base is triethyl amine, pyridine or sodium carbonate. Preferably, the mixture is stirred at a temperature of 0 ° C to 60 ° C, more preferably, at a temperature of 20 ° C to 24 ° C. Preferably, the mixture is stirred for 12 hours to 48 hours, more preferably, the mixture is stirred for 12 hours to 22 hours. Compound VIII can be isolated by any method known to the person skilled in the art. These methods include, but are not limited to, neutralizing the mixture by adding a basic aqueous solution, separating the organic and aqueous phase, washing the organic phase with water, filtering the organic phase, and concentrating the organic phase under vacuum. Isolated compound VIII contains an impurity selected from the group consisting of: compound VII: compound IX and mixtures of them. Preferably, compound VII is present in crude compound VIII in an amount not greater than 1.7% area by HPLC, more preferably, from 0.2% to 1.24% area by HPLC. Preferably, compound IX is present in an amount not greater than 7%, more preferably, from 1% to 5.2% area by HPLC.

Optionally, isolated compound VIII can be purified by crystallization from wet acetonitrile and dichloromethane, to give compound VIII having a purity of 90% to 99.9% area by HPLC.

Preferably, the level of compound VII in compound VIII can be significantly decreased by the preceding crystallization process. The compound VIII obtained by the preceding crystallization process contains an impurity selected from the group consisting of: compound VII, compound IX and mixtures thereof. Preferably, compound VII is present in an amount not greater than 0.3% area by HPLC, more preferably from 0.1% to 0.3% area by HPLC. Preferably, compound IX is present in an amount not greater than 1% area area by HPLC, more preferably, not more than 0.5% area by HPLC.

The carrying out of a second crystallization, which was described above, derives into compound VIII containing an impurity selected from the group consisting of: compound VII, compound IX and mixtures thereof. Preferably, compound VII is present in an amount not greater than 0.3% area by HPLC, more preferably not greater than 0.2% area by HPLC. Preferably, compound IX is present in an amount not greater than 0.3% area by HPLC, more preferably from 0.1% to 0.3% area by HPLC.

Preferably, the wet acetonitrile contains 1% to 5% water by volume, more preferably 1% to 1.25% water by volume.

The process for the preparation of compound VIII, more preferably compound VII, can be carried out on an industrial scale.

The invention comprises a process for the synthesis of rocuronium bromide (Compound I), wherein the quantity of collateral products is minimized. Collateral products include compounds such as which are obtained when a large excess of allyl bromide is used.

The process of the invention has a 95% molar yield of rocuronium bromide, which is obtained by precipitation from a mixture of dichloromethane and diethyl ether. Precipitation avoids complex or time-consuming purification steps.

The process for preparing rocuronium bromide comprises combining Compound VIII, a polar aprotic organic solvent, allyl bromide, and at least one inorganic base to obtain a mixture; and isolate rocuronium bromide.

The Roe obtained by the preceding process has a purity of at least 94% area by HPLC, preferably from 99% to 100% area by HPLC. The polar aprotic organic solvent includes, but is not limited to, halogenated hydrocarbons, esters or ketones. A preferred halogenated hydrocarbon is a halogenated hydrocarbon of Ci-2, more preferably, dichloromethane. A preferred ester is a C3-4 ester, more preferably, ethyl acetate. Preferably, the ketone is a C3-4 ketone, more preferably acetone. The most preferred polar aprotic organic solvent is dichloromethane.

The amount of allyl bromide should be sufficient to give the desired product without forming large amounts of unwanted side products. Preferably, the allyl bromide is present in an amount of 1.3 to 3 mole equivalents for each mole of compound VIII, more preferably in an amount of 2 mole equivalents for each mole of compound VIII, instead of 8 equivalents of moles as used in the process disclosed in U.S. Patent No. 4,894,369.

Preferably, the mixture of compound VIII, the polar aprotic organic solvent and the allyl bromide has a low water content, more preferably, less than 0.1% water content by Karl Fischer, even more preferably less than 0, 05% water content, and more preferably, less than 0.03% water content. The presence of the organic base inhibits the competing reaction that provides unwanted byproducts, such as Additional collateral products include: E The presence of inorganic bases allows faster conversion under more moderate conditions, slowing down the speed of competing reactions that produce byproducts such as structures A-E (see the preceding schemes). Structure C is the protonated form of Roc-1 and its presence affects the potentiometric assay.

Optionally, compound VII, allyl bromide and the polar aprotic organic solvent can be treated separately with an inorganic base, before being combined. The inorganic base includes, but not limited to, alkaline and aluminum bases. More preferably, the alkaline base is sodium carbonate, sodium bicarbonate or potassium carbonate. A more preferred aluminum base is aluminum oxide. The most preferred organic base is sodium carbonate.

Preferably, the mixture is stirred at a temperature of 15 ° C to 40 ° C, more preferably, at a temperature of 35 ° C to 40 ° C.

Preferably, the mixture is maintained for 20 hours to 24 hours, more preferably for 22 hours to 24 hours.

The crude rocuronium bromide can be isolated by any method known to those skilled in the art. These methods include, but are not limited to, concentrating the reaction mixture, dissolving the residue with dichloromethane, and filtering the salts that are used in the reaction, such as sodium carbonate.

The crude Roe of the formula I obtained by the preceding process can be purified by a process comprising dissolving the crude rocuronium bromide in at least one polar aprotic organic solvent to form a solution; adding an optionally combined bleaching agent with a base to the solution to form a first suspension; filter the first suspension; add the resulting filtrate to an antisolvent; shake vigorously to obtain a second suspension; recover the solid Rocuronium bromide from the second suspension; and drying the wet Rocuronium bromide at a temperature not higher than 35 ° C.

Preferably, before using the decolorizing agent, the excess allyl bromide is removed from the crude Rocuronium bromide. The excess of allyl bromide can be removed from the crude Rocuronium bromide by dissolving the rocuronium bromide in at least one polar aprotic organic solvent, and removing the solvent, preferably by evaporation, to obtain an oily residue. The dissolution and removal of the solvent can be repeated as many times as necessary to remove the excess of allyl bromide. The polar aprotic organic solvent includes, but is not limited to, halogenated hydrocarbons, esters, or ketones. Preferably, the halogenated hydrocarbon is dichloromethane. A preferred ester is ethyl acetate. Preferably, the ketone is acetone. More preferably, the polar aprotic organic solvent is dichloromethane.

The decolorizing agent includes, but is not limited to, aluminum oxide, activated carbon, or silica gel. When the bleaching agent is not basic then a base can be used in combination with the bleaching agent. Preferably, the decolorizing agent is aluminum oxide. Preferably, the base is sodium bicarbonate.

The mixture of the filtrate with the antisolvent is made while stirring vigorously. The conditions for stirring "vigorously" depend on the size of the reaction vessel. On a small scale, for example a 100 ml flask, 800-1000 ppm corresponds to shake "vigorously". On a larger scale, for example a 1000 L flask, an impeller / agitator at 250 rpm in the presence of baffles can be considered to shake "vigorously". Vigorous agitation makes it possible to obtain a product that can be dried at a low residual solvent content.

Preferably, the antisolvent is selected from a group consisting of: ether, ester and aromatic hydrocarbon and mixtures thereof. Preferably, the preferred ether is diethyl ether or diisopropyl ether. Preferably, the ester is ethyl acetate. A preferred aromatic hydrocarbon is toluene. Preferably, the solvent in the filtrate is dichloromethane and the JQ antisolvent is diethyl ether. Generally, when the solvent is dichloromethane and the antisolvent is diethyl ether, the reaction gives from 112% to 118% w / w of rocuronium bromide.

Preferably, the rocuronium bromide is dried under vacuum j < - for at least 5 days at a temperature not exceeding 35 ° C.

The process for the preparation of Roe of the formula I, more preferably from the compound VIII, can be carried out on an industrial scale.

The present invention also comprises a process for the preparation of the quaternary ammonium salt, Roe, of the formula I 1 comprising combining a starting Compound VI containing 10% to 40% area by HPLC of Compound Vl-a with an organic solvent miscible with water to obtain a suspension; stir the suspension at a temperature of 60 ° C to 80 ° C to obtain a mixture; add water to the mixture; isolating Compound VI from the mixture, wherein Compound VI isolated with less than 3% area by HPLC of Compound VI-a; forming a solution of Compound VI with less than 3% of the compound Vl-a and an organic solvent miscible with water optionally combined with an organic solvent immiscible with water; add at least one reducing agent to the solution at a temperature of -15 ° C to 10 ° C to obtain a mixture; stir the mixture at a temperature of 20 ° C to 24 ° C; isolating Compound IV from the mixture having a purity of at least 85% area by HPLC; forming a suspension of Compound IV, morpholine, and at least one acid catalyst; shake the suspension at a temperature of 100 ° C at reflux temperature for 24 hours at 48 hours; isolating Compound VII from the suspension; combining Compound VII, a polar organic solvent, and at least one acetylating agent with at least one base to obtain a mixture; isolating Compound VII from the mixture; combining Compound VII, a polar aprotic organic solvent, allyl bromide, and at least one inorganic base to obtain a mixture; and isolate rocuronium bromide. While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present claimed invention accordingly includes variations from the particular examples and preferred embodiments described herein, as is apparent to one skilled in the art.

E ploses X-ray diffraction analysis of 2a, 3a - ????? - 16ß- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI X-ray powder diffraction (PXRD) was performed on an ARL X-ray diffractometer model X'TRA-030, T-T goniometer, Cu tube, solid state detector with Peltier cooling. The sample holder was a standard circular aluminum sample holder with a quartz plate with zero circular background with a cavity of 25 (diameter) X 0.5 mm (depth). Scan parameters: Range 2-40 degrees two theta, scanning mode: continuous scan and scanning speed: 3 degrees / minute.

Differential Scanning Calorimetry (DSC) The differential scanning calorimetry was performed in DSC 822e / 7700, Mettler Toledo with sample weight: 3-5 mg. The heating rate: 10 ° C / minute, and the number of holes in the crucible was 3. The N2 current: the flow rate was 40 ml / minute and the scan range was 30 ° C-250 ° C.

Thermal Gravimetric Analysis (TGA) The thermal gravimetric analysis was performed in a TGA / SDTA 851% Mettler Toledo and the weight of the sample was 7-15 mg. The heating rate was 10 ° C / minute, and the flow velocity of the N2 stream was: 50 ml / minute. The exploration range was 25 ° C-250 ° C.

Example 1: Preparation of the mixture of 2a, 3a-epoxy-163- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI, and 2a, 3a-epoxy-16a- (1-pyrrolidinyl) -5a- androstan-17-one, Compound VI-a To a solution of 2a, 3a, 16a, 17a-bisepoxy-5a-androstan-17p-ol acetate III (50 g, 144.32 mmol) in methanol (500 mL) was added a 4 N solution of sodium hydroxide (40 mL, 9.525, 158.75 mmol) at 20 ° C-24 ° C and under a nitrogen atmosphere. The mixture was heated to reflux (60 ° C-65 ° C) for 30 minutes, and then cooled to 40 ° C and pyrrolidine (24 mL, 288.64 mmol) was added. The reaction mixture was heated to reflux (60 ° C-65 ° C) for 30-45 minutes, then cooled to room temperature and then ice-water (500 mL) was added, to obtain a suspension. The suspension was stirred at 5 ° C for 30 minutes and then the solid was filtered and washed with cold water (2 x 200 mL). The wet solid was dried under vacuum to give 47 g of Compound VI as a pale yellow powder having a Vl-a to VI ratio of 18:82.

Example 2: Balancing process to obtain 2a, 3a-epoxy-16p- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI The dried compound of Example 1 (47 g) was suspended in methanol (235 mL) and refluxed (60 ° C-65 ° C) between 20-30 minutes. Water (715 mL) was added over a period of 20 minutes, and the resulting mixture was heated at 65 ° C-70 ° C for 30 minutes. The suspension formed was cooled to 0 ° C-5 ° C over a period of 30-40 minutes and the suspension was further stirred at this temperature for 20 minutes. The suspension was filtered and washed with water (188 mL). The wet solid was dried under vacuum to give 43 g (120.26 mmol, 83% yield, 93% purity by HPLC, having a melting point of 146 ° C) of Compound VI as a white solid, which has a ratio of Vl-a to VI of 1.8: 98.2. [α] D20 + 101.1 (c = 1, 0 in CHC13).

Example 3: Preparation of 2a, 3a-epoxy-16 - (1-pyrrolidinyl) -5a-androstan-ß-β-γ, Compound IV A suspension of 1 g (2.8 mmol) of Compound VI in methanol (20 mL) was cooled to -10 ° C, and then sodium borohydride (200 mg, 5.04 mmol) was added carefully in portions., under a nitrogen atmosphere. The mixture of the resulting heterogeneous reaction was allowed to react at 20 ° C-24 ° C and was stirred for at least 3 hours. The reaction mixture was diluted with CH2Cl2 and then purified water was added at 20 ° C-22 ° C. The solution was stirred for 10 minutes and then the phases separated. The organic phase was washed with purified water and the solution was concentrated under vacuum to give the desired crude Compound IV. The product was dried in a vacuum oven at 40 ° C for at least 16 hours to give 1 g (0.00278 mol) of a white solid (99.3% yield) containing the product IV 98.5% and the isomer IV-a 1.1% area by HPLC. Melting point: 171 ° C; [] D20 + 34, 0 (c = l, 0 in CHCI3). The structure was confirmed by the spectrometric analysis.

The characterization data of 2a, 3a-epoxy-16a- (pyrrolidin-1-yl) -17p-hydroxy-5a-androstane of Compound IV-a ^ -NMR (300 MHz, CDC13) C NMR (300 Hz, CDC13): The characterization data of: 2a, 3a-epoxy-16a- (pyrrolidin-1-yl) -17a-hydroxyl-5a-androstan of Compound IV-b C24H41NO2 Exact Mass: 375.31 Molecular Weight: 375.59 C, 76.75; H, 11.0; N, 3.73; 0, 8.52 1 H-NMR (300 MHz, CDC13) C NMR (300 MHz, CDC13) Example 4: Preparation of 2a, 3a-ββ-16β- (1-pyrrolidinyl) -5a-androstan-17 -ol, Compound IV The title compound was prepared as a solid following the procedure of Example 3 and using Ethanol as solvent; melting point: 154.5 ° C; [a] D20 + 29.5 ° (c = 1, 0 in CHC13).

Example 5: Preparation of 2a, 3a-ββ-16β- (1-pyrrolidinyl) -5a-androstan-17 -ol, Compound IV The title compound was prepared as a solid following the procedure of Example 3 and using isopropanol as solvent; melting point: 158 ° C; [a] D20 + 33, 6 ° (C = 1.0 in CHC13).

Example 6: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1β, Compound VII A suspension of 2a, 3a-e ???-16β - (1-pyrrolidinyl) -5a-androstan-17β-β1 (1.80 kg, 5.006 mol) in a mixture of morpholine (11.44 L) and purified water (1.144 L) was prepared at 20 ° C-24 ° C and under an atmosphere of N2. To the suspension was added p-toluenesulfonic acid (1.24 Kg, 6.508 mol) at 20 ° C-24 ° C and under an atmosphere of N2. The suspension was stirred in the dark and heated to reflux (100 ° C-110 ° C) for 4 hours. After 40 hours the reaction mixture was cooled to 20 ° C-24 ° C and poured into a second vessel maintained at 4 ° C containing 2% sodium carbonate solution (128 L), while He was shaking vigorously. The resulting suspension was stirred for 1 hour at 4 ° C. The solid obtained was filtered under vacuum, washed with cold purified water (100 L) and dried in a vacuum oven at 40 ° C for at least 48 hours, to give 2.07 Kg (4.49 mol) of a white solid (89.7% molar yield and purity of 94.12% area by HPLC) melting point 225 ° C; [cc] D20 +82, 0 ° (c = l, 02 in CHC13). The product could be used in the next stage without further purification.

The obtained product was further crystallized from methanol then subjected to crystal-only X-ray crystallography analysis which confirmed the stereochemistry of the product. 0.42% area by HPLC Unidentified impurity 5.16% area by HPLC. Unidentified impurities 0.29% area by HPLC.

Example 7: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, compound VII The title compound was prepared as a solid following the procedure of Example 6 and using methanesulfonic acid as a catalyst; melting point 230 ° C.

Example 8: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, Compound VII The title compound was prepared as a solid following the procedure of Example 6 and using sulfuric acid as a catalyst; melting point 230 ° C; [] D20 +83, 8 ° (c = l, 02 in CHCI3). The purity of the crude product by HPLC of 97.36% area. The crude product contained the following impurities: 0. 503% a / a 0. 15% a / a 0.37% a¾ Example 9: Preparation of 2ß- (4-morpholinyl) -? β-81-pyrrolidinyl) - Sot-androstan-Sa, 17β-1, Compound VII The title compound was prepared as a solid following the procedure of Example 6 and using hydrochloric acid as a catalyst; melting point 226 ° C; [cc] D20 + 81.3 ° (c = 1, 02 in CHC13). The purity of the crude product by HPLC is 94.23% area. The crude product contained the following impurities: 0. 453% a / a 0.62% a / a 0.50% a / a Example 10: Preparation of 2β- (4-morpholinyl) -163- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, Compound VII The title compound was prepared as a solid following the procedures of Example 6 and using zinc acetate as a catalyst; melting point 218 ° C. The purity of the crude product by HPLC is 77.42% area. The crude product contained the following impurities: 6. 87% a / a 0.92% aa 0.47% .a / a and 0.82% area by HPLC of the starting material.

Example 11: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, Compound VII The title compound was prepared as a solid following the procedure of Example 6 and using ferric chloride as a catalyst; melting point 216 ° C. The purity of the crude product by HPLC is 89.0% area. The crude product contained the following impurities: 0. 97% a / a And 0.76% area by HPLC of the starting material.

Example 12: Preparation of 2β- (-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, Compound VII The title compound was prepared as a solid following the procedure of Example 6 and using standard conditions and NaOH during workup; 229 ° C point; [a] D20 +83, 5 ° (c = l, 02 in CHC13). The purity of the crude product by HPLC is 97.17 area%. The crude product contained the following impurities: 0 * 10% a / a Example 13: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, Compound VII The title compound was prepared as a solid following the procedure of Example 6 and using the standard conditions; melting point 225 ° C; [a] D20 + 81.3 ° (c = l, 02 in CHC13). The purity of the crude product by HPLC is 94.45% area. The crude product contained the following impurities: 033% a / a 0.39% e / a and 1.01% area by HPLC of the starting material.

Example 14: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII To a suspension of 2β- (-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1 (2.067 Kg, 4.628 mol) in dichloromethane (103.35 L) at 20 ° C -22 ° C, triethylamine (1.935 L, 13.883 mol) was added under an N2 atmosphere. The mixture was stirred until complete dissolution. Acetic anhydride (0.875 L, 9.255 mol) was charged slowly under continuous stirring and then the resulting reaction mixture was stirred for 22 hours at a temperature of 20 ° C-22 ° C. Then a 5% Na2CO3 solution (41.34 L) was added and the mixture was stirred for 5-10 minutes. The phases were separated and the organic phase was washed with water (2 x 41 L) at 15 ° C, dried with anhydrous Na 2 SO 4 (10 Kg) and filtered under vacuum to remove salts, which were rinsed with dichloromethane (10 L) . The solvent was removed under vacuum at a temperature below 20 ° C until a final volume of 12 L. was obtained. To the stirred solution concentrated at a maximum temperature of 20 ° C was added wet acetonitrile (40 L), then concentrated under vacuum at a temperature below 15 ° C, at a total volume of 40 L of a suspension. The resulting suspension was cooled to 0 ° C-5 ° C, stirred for 1 hour, filtered under vacuum and washed with acetonitrile (3 L). The desired wet product was dissolved in dichloromethane (9: 5 L) at 20 ° C-22 ° C, then acetonitrile (38 L) was added. The volume was reduced under vacuum at a temperature below 15 ° C to a total volume of 39 L to give a suspension. The resulting suspension was cooled to 0 ° C-5 ° C and stirred for 1 hour. The solid obtained was filtered under vacuum and the product was washed with acetonitrile (3 L). The crude product was dried in a vacuum oven at 40 ° C for at least 15 hours to give 1.51 Kg of a white solid (68.8% of molar yield and a purity of 99.9% by HPLC); melting point 160 ° C; [a] D20 +55, 5 (c = 1, 0 in CHC13).

Example 15: Preparation of 2β ~ (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII The title compound was prepared as a solid following the procedure of Example 14 and using acetyl chloride and triethylamine, defusion point 155 ° C; [a] D20 +54, 3 (c = l, 0 in CHC13). The purity of the purified product is 97.48% area by HPLC containing the impurities: VII 1.24% area by HPLC and IX 1.05% area by HPLC.

Example 16: Preparation of: 2ß- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII The title compound was prepared as a solid following the procedure of Example 14 and using acetic anhydride and pyridine; melting point 147, 5 ° C; [O] D20 +50, 7 (c = 1, 0 in CHC13). The purity of the purified product is 93.92% area by HPLC containing the impurities: VII 0.88% area by HPLC and IX 5.19% area by HPLC.

Example 17: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII The title compound was prepared as a solid following the procedure of Example 14 and using acetic anhydride and sodium carbonate; melting point 153, 5 ° C; [a] D20 +50, 9 (c = l, 0 in CHCI3). The purity of the purified product is 97.11% area by HPLC containing the impurities: VII 0.23% area by HPLC and IX 2.64% area by HPLC.

Example 18: Preparation of 2β ~ (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3, 17p-diol 17-acetate, Compound VIII The procedure of Example 13 was repeated using ethyl acetate as solvent. The residue obtained, determined by HPLC, was a mixture of 25.37% of the desired Compound VIII, 4.4% of Compound IX and 49.26% of Compound VII.

Example 19: Preparation of 2ß ~ (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII The procedure of Example 13 was repeated using isobutyl acetate as solvent. The residue obtained, determined by HPLC, was a mixture of 23.74% of the desired compound VIII, 11.52% of Compound IX and 17.34% of Compound VII.

Example 20: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII The procedure of Example 13 was repeated using methyl isobutyl ketone as solvent. The residue obtained, determined by HPLC, was a mixture of 35.0% of the desired Compound VIII, 6.9% of Compound IX and 17.0% of Compound VII.

Example 21: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII ? The procedure of Example 13 was repeated using dichloromethane as the solvent and a 0.1% w / w of water was added on purpose. After a reaction time of 22 hours, the residue obtained was a mixture of 90.54% of the desired Compound VIII, 3.70% of Compound IX and 3.99% of Compound VII determined by HPLC.

B. The procedure of Example 13 was repeated using dichloromethane as a solvent and 0.5% w / w of water was added on purpose. After a reaction time of 22 hours, the residue obtained was a mixture of 87.41% of the desired Compound VIII, 2.26% of Compound IX and 8.79% of Compound VII determined by HPLC.

The results are summarized in the following tables: Table 1. HPLC after a reaction time of 22 hours Table 2. HPLC after a reaction time of 41 hours Example 22: Preparation of 2β- (4-morpholinyl) -16β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β - ??? 1 17-acetate, Compound VIII The procedure of Example 16 was repeated using dichloromethane as a solvent and 1% w / w of water was added on purpose. After a reaction time of 22 hours, the residue obtained was a mixture of 88.8% of the desired Compound VIII, 1.90% of Compound IX and 7.77% of Compound VII determined by HPLC. hydroxy-2- (4-morpholinyl) -5a ^? 5? 3 -16β-?] -1- (2-propenyl) pyrrolidinium, Compound I A solution of 2β ~ (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate (10 g, 0.02 mol) in dichloromethane (150 ml) was prepared at 20 ° C-22 ° C under an atmosphere of N2. Then, 75 mL were distilled at normal pressure. At the same time, a solution of allyl bromide (3.5 mL, 0.04 mol) in dichloromethane (25 mL) was prepared and mixed with sodium carbonate (5%)., 2 g, 0.04 mol), then stirred for 30 minutes at room temperature. The suspension was filtered through a 0.45 μ filter. and to the solution of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3, 17β-1α-acetate (10 g, 0.02 mol) in dichloromethane was added. The reaction was poured into a Schott amber flask, purged, sealed and stirred for 22 hours at 40 ° C. The mixture was then cooled to room temperature and concentrated under vacuum keeping the temperature below 20 ° C. Dichloromethane (50 mL) was added to the flask and then concentrated under vacuum maintaining the temperature below 20 ° C.; this procedure was repeated twice. The residue was dissolved at room temperature and a nitrogen atmosphere in dichloromethane (111 mL) was filtered through a 0.45 μp membrane? and added slowly to diethyl ether (745 mL) with continuous stirring.

The resulting suspension was stirred for 30 minutes and filtered under a nitrogen atmosphere. The solid obtained was dried at 35 ° C for 60 hours to give 11.8 g (118% w / w, 94.58% mol / mol, 99.4% purity by HPLC) containing Impurity A 0.1 %, Impurity B 0.1% area by HPLC; Impurity E 0.1% area by HPLC) of a whitish solid, melting point 209 ° C; [cc] D20 +29, 8 ° (0 = 1.0 in CHC13).

Impurity A Impurity B Impurity E Example 24: Preparation of 1- [17p-acetyloxy-3a-hydroxy-2 (4-morpholinyl) -5a-androstan-16P-yl] -1 (2-propenyl) pyrrolidinium bromide, Compound I The title compound was prepared as a solid following the procedure of Example 14 and using acetone as the reaction solvent, melting point 206 ° C; [a] D20 +29, 3 ° (c = l, 0 in CHCI3). The purity of the product is 99.5% area by HPLC, which contains Impurity A 0.1% area by HPLC; Impurity B 0.1% area by HPLC; and Impurity F 0.1% area by HPLC.

Impurity F Example 25: Preparation of 1- [17P-acetyloxy-3-hydroxy-2- (4-morpholinyl) -5a-androstan-16β-yl] -1 (2-propenyl) pyrrolidinium bromide, Compound I, base in situ A glass reactor was charged with 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1-acetate-17, Compound VIII (8.65 Kg, 17.7 mol ) and dichloromethane (130 L) at 20 ° C-22 ° C under an N2 atmosphere. Then, 40 L of dichloromethane were distilled at 32 ° C-35 ° C under normal pressure and the solution was allowed to reach 20 ° C-25 ° C. The volume was replaced with 40 L of dichloromethane and the same volume was scraped at 32 ° C-35 ° C, the mixture was cooled to 20 ° C-25 ° C. Sodium carbonate (8.65 Kg) was added to the reactor and the resulting mixture was stirred for 5 minutes. Then | allyl bromide (4.28 Kg) was added. The resulting suspension was stirred for 24 hours at 32 ° C-35 ° C. The mixture was then cooled to room temperature (20 ° C-25 ° C) and filtered under vacuum to remove the salt that was rinsed with dichloromethane (8.65 L). The solvent mixture was removed under vacuum maintaining the temperature below 20 ° C. The oily product was dissolved with dichloromethane (45 L) and concentrated in vacuo keeping the temperature below 20 ° C; this procedure was repeated twice. Once again the residue was dissolved at room temperature under a nitrogen atmosphere in dichloromethane (86.5 L) and aluminum oxide (4.32 Kg) was added, the resulting mixture was stirred at 20 ° C-22 ° C during 30 minutes and then it was filtered. The solution was slowly added to a glass reactor containing diethyl ether (452 L) with continuous stirring. The resulting suspension was stirred for 30 minutes and filtered under a nitrogen atmosphere. The obtained solid was dried at 35 ° C for at least 5 days to give 9.70 Kg (0.016 mol, 112.13% w / w yield, 89.88% molar yield) of a whitish solid, which has a purity of 99.9% area by HPLC, which contains Impurity A 0.1% area by HPLC, and Impurity B 0.1% area by HPLC.

Example 26: Comparative Example: Preparation of 2β- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII, according to Example 7 of U.S. Patent No. 4,894,369 Acetyl chloride (0.179 mL) was added to a solution of compound VII (1.0 g) in dichloromethane (40 mL) and the reaction was set aside at room temperature for 29 hours ( TLC analysis was performed during the course of the reaction). The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (19.4 mL). The solution was washed with 5% sodium carbonate solution (20 mL) and water (2x20 mL), dried (a2S04) and evaporated to dryness to give a gum (1.18 g). The crude product showed an HPLC profile containing compound VIII with a purity of 81.56% area, starting diol, compound VII, in an amount of 5.16% area and the impurity impurity of diacetate, compound IX , in an amount of 11.93% area.

Example 27: Comparative example: preparation of (2a, 3a, 5a, 16β, 17β) -2, 3-epoxy-16- (1-pyrrolidinyl) androstan-17-ol, Compound IV according to Example 1 of U.S. Patent No. 4,894,369 ? a suspension of compound III (10 g) in methanol (100 mL) was added a solution of sodium hydroxide (10 mL, 4N) at room temperature. The reaction mixture was heated under reflux for 30 minutes. The reaction mixture was then cooled to 40 ° C and pyrrolidine (15 mL) was added. The reaction mixture was heated under reflux for 15 minutes. The reaction mixture was cooled to 10 ° C and then sodium borohydride (2 g) was added. The reaction mixture was warmed to room temperature and stirred for two hours. Water (200 mL) was added and the resulting solid was filtered and washed with water (3x100 mL). The solid was dried under vacuum overnight to give a white product (9.6 g) having an HPLC purity of: Compound IV (75.12% area), Compound IV-a (11.62%) and Compound IV-b (4.89% area). 2Q Crystallization of the crude product from acetone (250 mL) gave 5.3 g of a white solid having a HPLC purity of: Compound IV (92.20% area), Compound IV-a (2.13% area) and Compound IV-b (0.82% area). ^ 5 Compound 28: Preparation of 2g, 3a-epoxy-16p- (1-pyrrolidinyl) -5a-androstan-17 -ol, Compound IV Step (a): Synthesis of Compound VI g of 2a, 3a, 16a, 17a-bisepoxy-5a-androstan-17-acetate (28.86 mmol) were dissolved in 100 ml of methanol at 20 ° C-22 ° C under stirring. Then 8 ml of 4N sodium hydroxide (32 mmol) was added. The mixture was then heated to reflux and maintained at reflux temperature for 30 minutes. The mixture was then cooled to 35 ° C and 4.8 ml of pyrrolidine (57.37 mmol) was added. Then, the mixture was refluxed again and refluxed for 2 hours. The mixture was then cooled to 30 ° C then poured into a flask containing 600 ml of cold water (3 ° C-6 ° C). The reaction flask was washed with 20 ml of methanol, which was then poured into the flask in which the reaction mixture was poured. The mixture was then kept under stirring at 3 ° C-6 ° C for 40 minutes. The resulting solid was then collected by filtration and washed with 40 ml of cold water. The solid was then dried on the filter with suction for at least 12 hours and the wet solid was used in the next step. Obtained: 9.5 g of the mixture of VI with Vl-a in a ratio of 86:14.

Step (b): Isomer balance of Compound VI 9.5 g of the wet solid mixture of VI and Vl-a obtained in step (a) were suspended in 47.5 ml of methanol (5 volumes), then the mixture it was heated to reflux temperature and refluxed for 20 minutes. Then for a period of 90 minutes 142.5 ml of water (15 volumes) were added slowly, allowing the reflux temperature to rise during the aggregation. Then, the mixture was kept under stirring for another 30 minutes at reflux temperature. The mixture was then cooled to 0 ° C-5 ° C for a period of 45 minutes. The solid was then collected by filtration and then washed with 38 ml of water. The solid was held on the filter under suction for 12 hours and then used in the next step. Obtained: 8.8 g of VI in an enriched isomeric ratio of 98.2: 1.8.

Step (c): Reduction to Compound VI to Compound IV In a flask, under a nitrogen atmosphere, load of 8.8 g (enriched isomeric ratio), 88 ml of methanol (10 volumes) and 44 ml of dichloromethane (5 volumes) ). The mixture was then stirred at 20 ° C-25 ° C until complete dissolution was achieved. The resulting solution was cooled to 0 ° C-5 ° C and then 1.70 g of sodium boron hydride (45 moles) was added in portions over a period of 10 minutes. The resulting mixture was then heated at 20 ° C-25 ° C for a period of 90 minutes and kept under stirring for another 60 minutes.

Then some of the solvents were distilled under vacuum at an internal temperature less than or equal to 40 ° C, until a residual volume of 79.2 ml was achieved. Then 35.2 ml of methanol were added to the mixture. Then the solvents were distilled under vacuum, until a residual volume of 79.2 ml was achieved. The mixture was then heated to 25 ° C and 352 ml of demineralized water were added under stirring for a period of 1 hour. The resulting suspension was then cooled to -2 ° C / + 2 ° C for a period of at least 30 minutes, and the suspension was kept under stirring at this temperature for another 90 minutes. The solid was then collected by filtration and the filter cake was washed with 35 ml of demineralized water. After drying (16 hours, 40 ° C, under vacuum), 8.3 g of IV were obtained (yield 5 of 80.6%). This sample showed 0.83% of IV-a; 0.49% of IV-b; 1.91% of IV-c; and unknown 3.3%.

Step (d): Final Purification of Compound IV Under nitrogen, 8.3 g of IV from step (c) were charged into a flask and ^ 104 ml of dichloromethane were added. The mixture was then heated to 30 ° C until complete dissolution was achieved. Then 7.0 ml of 0.01M HC1 was added to the mixture and the mixture was stirred for 30 minutes to complete the extraction. The aqueous layer was separated from the resulting biphasic system and discarded. The organic layer was washed with 2.4 ml of 0.1 M HC1 and the aqueous layer was separated and discarded. The organic layer was then washed with 2.5 ml of water, and the aqueous layer was separated and discarded. The organic layer was then heated to reflux temperature, and 71 ml of the solvents were distilled from the organic layer for a period of 1 hour. Then 104 ml of methanol was added. The solution was then heated to reflux temperature and 59 ml of the solvents were distilled over a period of 1 hour. Then, while maintaining the temperature at 50 ° C, 33 ml of demineralized water was added over a period of 15 minutes.

The resulting non-transparent mixture was then cooled to 25 ° C over a period of 1 hour. The solution was then cooled to 0 ° C / -2 ° C for a period of 1 hour and kept at this temperature for 60 minutes. The solid was then collected by filtration and washed with 33 ml of demineralized water. After drying the product for 16 hours at 40 ° C under vacuum, 8.0 g of pure IV were obtained (IV-a 0.10%, IV-b 0.10%, IV-c 0.58%). %.

The analysis of 2a, 3a-γ-16β- (1-pyrrolidinyl) -5a-androstan-17-one, Compound VI and the mixture of the equilibrium reaction of 2a, 3a-epoxy-16a- ( 1-pyrrolidinyl) -5a-androstan-17-one, Compound VI-a, and 2a, 3a-α-β-β-β-1-pyrrolidinyl-5a-androstan-17-one, Compound VI. The HPLC conditions were as follows. The packing column was X Terra MS C18; 5 μp? x 4.6 mra catalog N ° 18600494 or equivalent. Eluent A was water and eluent B was methanol / NHaOH 100: 1 (v / v). The composition of the eluent was A: B 20:80 (v / v). The stop time was 20 minutes, the flow rate 0.8 mL / minute, ultraviolet radiation detector at 210 nm, the temperature of the column was 30 ° C and the volume of the injection was 20 μ? .

The analysis of 2a, 3a-γ-16β- (1-pyrrolidinyl) -5a-androstan-17p-ol, Compound IV was performed with a column packing X Terra S C18; 5 u, 250 mm x 4.6 mm catalog No. 18600094 or equivalent. Eluent A was water and eluent B was methanol (NH40H, 28%) 100: 1 (v / v). The composition was A: B 20:80 (v / v). The stop time was 45 minutes, the flow rate was 0.8 mL / minute, the detector was ultraviolet radiation at 210 nm, the temperature of the column was 30 ° C and the volume of the injection was 10 μ? .

The analysis of 2ß- (4-morpholinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1, Compound VII was performed with a column packing X Terra MS C18; 5 μm, 250 mm x 4.6 mm catalog No. 18600494 or equivalent. The eluent A was water and the eluent B was methanol / NH 4 OH 100: 1 (v / v), the composition was A: B 10:80 (v / v). The stop time was 45 minutes, the flow rate was 0.8 ml / minute, the detector was ultraviolet radiation at 210 nm, the temperature of the column was 30 ° C and the volume of the injection was 20 μ? .

The analysis of 2β- (4-mo folinyl) -16β- (1-pyrrolidinyl) -5a-androstan-3a, 17β-1α-acetate, Compound VIII was performed with a Hypersil silica column packing; 5 μp ?, 350 mm x 4.6 mm, catalog No. 30005-254630 or equivalent. Eluent A was tetramethylammonium hydroxide buffer, eluent B was acetonitrile and the composition was A: B 25:75. The stop time was 20 minutes, the flow rate was 1.0 mL / minute, the detector was ultraviolet radiation at 210 nm, the temperature of the column was 30 ° C and the volume of the injection was 10 μ ?.

The analysis of rocuronium bromide, Compound I, was carried out with a packed column Hypersil silica; 5 μm, 250 mm x 4.6 mm, Catalog No. 30005-254630 or equivalent. Eluent A was tetramethylammonium hydroxide buffer, 0.05M, pH 7.4, eluent B was acetonitrile and the composition was 10:90 A: B. The stop time was 25 minutes, the flow rate was 2.0 mL / minute, the detector was aviolesta ult radiation at 210 nm, the column temperature was 30 ° C, and the volume of the injection was 5 minutes. μ? .

Example 29: Reference Example: Transformation of Compound VI into Compound IV (Example 1 of U.S. Patent No. 4,894,369) A solution of sodium hydroxide (150 ml, 4N) was added to a suspension of (2a, 3a, 5a, 16β, 17a) -2, 3, 16, 17-bisepoxy-androstan-17-ol acetate (150 g) in methanol (1.5 1) and the mixture was heated under reflux for 30 minutes. When the solution had cooled to 40 ° C, pyrrolidine (225 ml) was added and the solution was heated under reflux for another 15 minutes. The solution was cooled to 10 ° C by means of an ice bath, and sodium borohydride (30 g) was added in portions with stirring, keeping the temperature below 20 ° C. The solution was stirred for 2 hours at room temperature, then water (3 1) was added to precipitate the product, which was filtered and washed with water (3x 1 1). A solution of the crude solid in dichloromethane (11) was washed neutral with water (2x1 1), dried (Na 2 SO 4) and evaporated to dryness. The crystallization of the resulting white solid from acetone gave (2a, 3a, 5a, 16β, 17β) -2, 3-epoxy-16- (1-pyrrolenyl) -androstan-17-ol (85.2 g), melting point 156 ° C-160 ° C; [a] D20 +33, 6 ° (c 1, 05 in CHC13).

Example 30: Reference Example: Transformation of Compound IV into Compound VII (Example 3 of U.S. Patent No. 4,894,369) Water (50 mL) was added to a solution of (2a, 3a, 5a, 16β, 17β) 2, 3-epoxy-16- (1-pyrrolidinyl) -androstan-17-ol (85.2 g) in morpholine (500 ml) and the reaction mixture was heated to reflux temperature for 3 days. Evaporation of the reaction mixture gave a crude product, which was crystallized from acetone. Recrystallization from methanol gave (2β, 3a, 5a, 16β, 17β) -2- (4-morpholinyl) -16- (1-pyrrolidinyl) -androstan-3, 17-diol (71.2 g), melting point 212 ° C-219 ° C; [a] D20 = + 87, 9 ° (c 1.02 in CHC13).

Example 31: Reference Example: Transformation of Compound VII into Compound VIII (Example 7 of U.S. Patent No. 4,894,369) Acetyl chloride (9.63 mL) was added to a solution of (2ß, 3a, 5a, 16β, 17β) -2- (4-morpholinyl) -16- (1-pyrrolidinyl) -androstan-3,17-diol (53.5 g) in dichloromethane (2.14 1) and the reaction was removed at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (500 ml). The solution was washed with 5% sodium carbonate solution (500 ml) and water (2 × 500 ml), dried (Na 2 SO 4) and evaporated to dryness to give a gum (59.9 g), which was subjected to chromatography. on alumina (type Fluka 5016A) (50g). Crystallization of the material, from pure fractions, from diethyl ether-n-hexane gave (2β, 3a, 5a, 16β, 17β) -2- (4-morpholinyl) -16- (1-pyrrolidinyl) -androstan-3, 17 -diol 17-acetate (28.0 g), melting point 149 ° C-153 ° C. [] D20 = +54, 0 ° (c 1.03 in CHCI3).

Example 32: Reference Example: Transformation of Compound VIII into Compound I (Example 23 of U.S. Patent No. 4,894,369) 2-Propenyl bromide (1.95 mL) was added to a solution of (2ß, 3a, 5a, 16ß, 17ß) -2- (4-morpholinyl) -16 (1-pyrrolidinyl) -androstan-3, 17- diol 17-acetate (1.35 g) in dichloromethane (27 ml) and the solution was sealed in a pressure flask at room temperature for 22 hours. The solvent was removed under reduced pressure with the minimum heating and the crude solid (1.59 g) was subjected to chromatography on alumina (type Fluka 5016A). The pure fractions were combined, taken up in dichloromethane (15 ml) and diethyl ether (100 ml) was added to precipitate 1- [(2β, 3a, 5a, 16β, 17β) -17-acetyloxy-3-hydroxybromide. 2- (4-morpholinyl) -androstan-16-yl] -1- (2-propenyl) -pyrrolidinium (1/14 g), mp 161 ° C-169 ° C; [a] D20 = + 18.7 ° (c 1.03 in CHCI3).

Claims (111)

1. A process for the preparation of the quaternary ammonium salt, Rocuronium bromide, of the formula I

saw

comprising: (a) combining a starting Compound VI having from 10% to 40% area by HPLC of Compound IV-a with an organic solvent miscible with water to obtain a suspension; (b) stir the suspension at a temperature of 60 ° C to 80 ° C to obtain a mixture) add water to the mixture; (d) isolating Compound VI from the mixture, wherein Isolated Compound VI has less than 3% area by HPLC of Compound VI-a; (e) forming a solution of Compound VI having less than 3% of the compound Vl-a and a water-miscible organic solvent optionally combined with an organic solvent miscible with water; (f) adding at least one reducing agent to the solution at a temperature of -15 ° C to 10 ° C to obtain a mixture; (g) stirring the mixture at a temperature of 20 ° C to 24 ° C; (h) isolating Compound IV from the mixture having a purity of at least 85% area by HPLC; (i) forming a suspension of Compound IV, morpholine, and at least one acid catalyst; (j) stirring the suspension at a temperature of 100 ° C under reflux for 24 hours at 48 hours; (k) isolating Compound VII from the suspension; (1) combining Compound VII, a polar organic solvent, and at least one acetylation reagent with at least one base to obtain a mixture; (m) isolating Compound VIII from the mixture; (n) combining Compound VIII, a polar aprotic organic solvent, allyl bromide, and at least one inorganic base to obtain a mixture; (o) and isolate rocuronium bromide from the mixture.

2. 2a, 3a - ????? - 1ßß- (1-pyrrolidinyl) -5a-androstan-17-one isolated, compound VI, of the following structure:

saw

3. The compound according to claim 2, characterized by the data selected from: a spectrum of 13 C-NMR having chemical carbon shifts at 218.3, 53.9, 52.2, 51.9, 50, 8, 47 , 5, 46, 9, 38, 1, 36.2, 34, 4, 33, 8, 31, 9, 30, 6, 28, 9, 28, 26, 6, 23.2, 20, 13, 9 and 12.9 ppm; a spectrum of 13 C-NMR that is substantially illustrated in Figure 5; a spectrum of "'' H-NMR having chemical shifts of hydrogen at 3.17-3.09, 2.92, 2.79, 2.64, 1.95-0.66, 0.9 and 0, 75 ppm, a 2H-NMR spectrum that is substantially illustrated in Figure 4, a mass spectrum (FAB (+), m / z) having a peak of MH + at 358.2, a mass spectrum illustrated substantially in Figure 7, an infrared radiation spectrum having peaks at 1736, 3452 and 1157 was "1" and an infrared radiation spectrum that is substantially illustrated in Figure 8.

4. A crystalline 2a, 3a-β-α-16β- (1-pyrrolidinyl) -5a-androstan-17-one, compound VI.

5. The crystalline 2a, 3a-ββ-16β- (1-pyrrolidinyl) -5a-androstan-17-one according to claim 4, characterized by powder X-ray diffraction peaks at 10.3, 14 , 8, 17.5, 18.4 and 19 degrees two theta, ± 0.1 degree two theta.

6. The crystalline 2a, 3a-ββ-16β- (1-pyrrolidinyl) -5a-androstan-17-one according to claim 4 or 5, also characterized by data selected from the group consisting of: diffraction peaks of X-ray powder at 10.9, 20.7, 22, 24.1, 26.9 and 27 degrees two theta, ± 0.1 degrees two theta; a powder X-ray diffraction that is substantially illustrated in Figure 1; a 0.2% weight loss, determined by TGA analysis; a TGA curve that is substantially illustrated in Figure 3; a DSC having a first endothermic peak of 35 ° C to 122 ° C and a second endothermic peak at 146 ° C; a DSC curve that is substantially illustrated in Figure 2 and a melting point of 155 ° C.

7. A process for increasing the isomeric ratio of Compound VI to Compound Vl-a comprising: (a) combining a starting compound VI containing 10% to 40% by HPLC of Compound VI-a with an organic solvent miscible with water for obtain a suspension;

(b) stirring the suspension at a temperature of 60 ° C to 80 ° C for a sufficient amount of time to obtain a solution; (c) adding water to the solution to form a suspension; Y

(d) isolating Compound VI from the mixture; wherein isolated Compound VI contains no more than 3% area by HPLC of Compound Vl-a

8. The process according to any of claims 1 and 7, wherein the starting compound VI contains 15% to 30% area by HPLC of the compound Vl-a.

9. The process according to any of claims 1 and 7 to 8, wherein the starting Compound VI contains from 10% to 20% area by HPLC of the compound Vl-a.

10. The process according to any of claims 1 and 7 to 9, wherein starting Compound VI contains 12% to 18% area by HPLC of Compound Vl-a.

11. The process according to any of claims 1 and 7 to 10, wherein the isolated Compound VI contains from 1% to 3% HPLC measuring area of the compound Vl-a.

12. The process according to any of claims 1 and 7 to 11, wherein the isolated Compound VI contains less than 2% area by HPLC of Compound Vl-a.

13. The process according to any of claims 1 and 7 to 12, wherein the isolated Compound VI contains less than 1% area by HPLC of Compound Vl-a.

14. The process according to any of claims 1 and 7 to 13, wherein the organic solvent miscible with water is a Ci_ alcohol.

15. The process according to claim 14, wherein the Ci_4 alcohol is methanol, ethanol, propanol, isopropanol or butanol and mixtures thereof.

16. The process according to claim 14 or 15, wherein the Ci_4 alcohol is methanol.

17. The process according to any of claims 1 and 7 to 16, wherein the suspension of step b, is stirred to a

5 temperature from 50 ° C to 70 ° C.

18. The process according to any of claims 1 and 7 to 17, wherein the water of step c is added dropwise to the mixture.

The process according to any of claims 1 and 7 to 18, wherein the water is added while maintaining the mixture at a temperature above 60 ° C.

j < - The process according to any of claims 1 and 7 to 19, wherein the water is added in an amount of 3 to 4 volumes of the volume of the organic solvent miscible with water.

21. The process according to any of claims 1 and 7 to 20, wherein the isolated compound of formula VI having less than 10% area by HPLC of Compound VI-a is converted to Rocuronium bromide.

22. A process for preparing Compound IV:

comprising: (a) forming a solution of Compound VI and an organic solvent miscible with water combined with an organic solvent immiscible with water; (b) adding at least one reducing agent to the solution at a temperature of -15 ° C to 10 ° C to obtain a mixture; (c) stirring the mixture at a temperature of 20 ° C to 24 ° C; and (d) isolating Compound IV from the mixture having a purity of at least 85% area by HPLC.

23. The process according to any of claims 1 and 22, wherein the organic solvent miscible with water is methanol and the organic solvent miscible with water is methylene chloride.

24. The process according to any of claims 1 and 22 to 23, which also comprises purifying Compound IV isolated by a process comprising: dissolving Compound IV in an organic solvent; extract the solution at least once with a mineral acid; heat the solution to reflux to distill 2/3 of the solvent; adding water to the solution at a temperature above room temperature to form a suspension; cooling the suspension to induce the precipitation of a solid; recover the solid from the suspension; and drying the solid to obtain Compound IV.

25. The process according to any of claims 1 and 22 to 24, wherein the isolated compound IV contains an impurity selected from the group formed by the compound IV-a,

IV-a

the compound IV-b,

the compound IV-c,

and mixtures of them.

26. The process according to claim 25, wherein the IV-a compound is present in an amount of less than 2% area by HPLC.

27. The process according to claim 25 or 26, wherein the compound IV-a is present in an amount of 1% to 2% area by HPLC.

28. The process according to any of claims 25 to 27, wherein the compound IV-b is present in an amount less than 1% area by HPLC.

29. The process according to any of claims 25 to 28, wherein the compound IV-c is present in an amount of less than 2% area by HPLC.

30. The process according to any of the claims

1 and 7 to 29, wherein the compound VI used as the material of

starting is with less than 10% area by HPLC, the composite

Vl-a, and compound IV obtained contains less than 2% area

5 by HPLC of compound Vl-a, less than 1% area by HPLC of compound IV-b, and contains less than 2% area by HPLC of compound VI-c.

31. The process according to any of claims 1 and 7 to 30, wherein the organic solvent miscible with water in a

Q straight or branched Ci_5 alcohol.

32. The process according to claim 31, wherein the Ci_5 alcohol is an alcohol of Ci_3.

^ 33. The process according to claim 32, wherein the C1-.3 alcohol is methanol, ethanol or isopropanol.

34. The process according to claim 32 or 33, wherein

C1-3 alcohol is methanol.

0

35. The process according to any of the claims

1 and 22 to 34, wherein the reducing agent is added to a

temperature from 0 ° C to -5 ° C.

36. The process according to any of claims 1 and 22 to 35, wherein the reducing agent is a metal hydride complex.

37. The process according to claim 36, wherein the metal hydride complex is an alkali metal hydride complex.

38. The process according to claim 37, wherein the alkali metal hydride complex is sodium borohydride, potassium borohydride or sodium trimethoxy borohydride.

39. The process according to claim 38, wherein the alkali metal hydride complex is sodium borohydride.

40. The process according to any of claims 33 to 39, which also comprises converting the compound IV having a purity of at least 85% area by HPLC into Rocuronium bromide.

41. A process to prepare Compound VII

Vile.

comprising: (a) forming a suspension of Compound IV, morpholine, and at least one acid catalyst; (b) stirring the suspension at a temperature of 100 ° C at reflux temperature for 24 hours at 48 hours; and (c) isolating Compound VII from the suspension.

42. The process according to any of claims 1 and 41, wherein the morpholine is in the form of an aqueous solution.

43. The process according to any of claims 1 and 41 to 42, wherein the catalyst is selected from the group consisting of mineral acid, organic acid and Lewis acid.

44. The process according to claim 43, wherein the organic acid is p-toluene sulfonic acid, methane sulfonic acid, trichloroacetic acid or trifluoroacetic acid.

45. The process according to claim 43 or 44, wherein the mineral acid is sulfuric acid or hydrochloric acid.

46. The process according to any of claims 43 to 45, wherein the Lewis acid is A1C13, ZnCl2, BF3, SnCl4, TÍCI4, AgC104, Zn (OAc) 2 or FeCl3.

47. The process according to any of claims 43 to 46, wherein the Lewis acid is zinc acetate or ferric chloride.

48. The process according to any of claims 1 and 41 to 47, wherein the catalyst is p-toluene sulfonic acid.

49. The process according to any of claims 1 and 41 to 48, wherein the suspension in step (j) of claim 1, and in step (b) of claim 41 is stirred at a temperature of 100 ° C. at 110 ° C.

50. The process according to any of claims 41 to 49, which also comprises converting compound VII to Rocuronium bromide.

51. A process for the preparation of Compound VIII

comprising: (a) mixing Compound VII, a polar organic solvent, and at least one acetylating reagent with at least one base to obtain a mixture; and (b) isolating Compound VIII from the mixture.

52. The process according to any of claims 1 and 51, wherein the isolated compound VIII contains an impurity selected from a group consisting of compound VII,

vn

the compound IX,

and mixtures of them.

53. The process according to claim 51 or 52, wherein the compound VII is present in an amount not greater than 1.7% area by HPLC.

54. The process according to any of claims 51 to 53, wherein the compound VII is present in an amount of 0.2% to 1.24% area by HPLC.

55. The process according to any of claims 51 to 54, wherein the compound IX is present in an amount not greater than 7% area by HPLC.

56. The process according to any of claims 51 to 55, wherein the compound IX is present in an amount of 1% to 5.2% area by HPLC.

57. The process according to any of claims 51 to 56, wherein Compound VII is obtained by the process according to claim 39 or by any other process.

58. The process according to any of claims 1 and 51 to 57, wherein the polar aprotic organic solvent is selected from the group consisting of ketone, ester, ether, amide, nitromethane and halogenated hydrocarbon.

59. The process according to claim 58, wherein the ketone is a ketone of € 3-5.

60. The process according to claim 59, wherein the C3-6 ketone is acetone or methyl isobutyl ketone.

61. The process according to any of claims 56 to 58, wherein the ester is an ester of C4-6-

62. The process according to claim 61, wherein the C 4-6 ester is ethyl acetate or isobutyl acetate.

63. The process according to any of claims 58 to 62, wherein the ether is a cyclic ester of C3_4.

64. The process according to claim 63, wherein the cyclic ether of C3-4 is tetrahydrofuran.

65. The process according to any of claims 58 to 64, wherein the amide is an amide of C3-4.

66. The process according to claim 65, wherein the C3-4 amide is N, N-dimethylformamide.

67. The process according to any of claims 58 to 66, wherein the halogenated hydrocarbon is a halogenated hydrocarbon of Ci-2.

68. The process according to claim 67, wherein the C1-2 halogenated hydrocarbon is dichloromethane or dichloroethane.

69. The process according to any of claims 1 and 51 to 68, wherein the polar aprotic organic solvent is dichloromethane.

70. The process according to any of claims 1 and 51 to 69, wherein the acetylation reagent is selected from the group consisting of acetyl halide, halogenated ester, anhydride and ester.

71. The process according to claim 70, wherein the acetyl halide is acetyl chloride.

72. The process according to claim 70 or 71, wherein the halogenated ester is AcOCH2CCl3, or AcOCH2CF3.

73. The process according to any of claims 70 to 72, wherein the anhydride is mixed anhydride or acetic anhydride.

74. The process according to any of claims 70 to 73, wherein the ester is isopropenyl acetate.

75. The process according to any of claims 1 and 61 to 74, wherein the acetylation reagent is acetyl chloride or acetic anhydride.

76. The process according to any of claims 1 and 51 to 75, wherein the base is an organic base.

77. The process according to claim 76, wherein the organic base is selected from the group consisting of aliphatic amine and aromatic amine.

78. The process according to claim 77, wherein the aliphatic amine is triethylamine, diethyl isopropylamine, tri-n-propylamine or tributylamine.

79. The process according to claim 77 or 78, wherein the aromatic amine is 4-dimethylaminopyridine.

80. The process according to any of claims 1 and 51 to 75, wherein the base is an organic base.

81. The process according to claim 80, wherein the inorganic base is selected from the group consisting of alkaline and aluminum bases.

82. The process according to claim 81, wherein the alkaline base is sodium carbonate or sodium bicarbonate.

83. The process according to claim 81 or 82, wherein the aluminum base is aluminum oxide.

84. The process according to any of claims 1 and 51 to 83, wherein the base is triethyl amine, pyridine or sodium carbonate.

85. The process according to any of claims 1 and 51 to 84, wherein the mixture in step (I) of claim 1, and in step (a) of claim 51 is stirred at a temperature of 0 ° C. at 60 ° C.

86. The process according to any of claims 1 and 51 to 85, wherein the mixture in step (I) of claim 1 and step (a) of claim 51 is stirred for 12 hours at 22 hours.

87. The process according to any of claims 1 and 51 to 86, which also comprises purifying compound VIII by crystallization from a mixture of wet acetonitrile and dichloromethane, then isolating it.

88. The process according to claim 87, wherein the wet acetonitrile contains from 1% to 5% water by volume.

89. The process according to claim 87 or 88, wherein the wet acetonitrile contains from 1% to 1.25% of aqua in and volume.

90. The process according to any of claims 87 to 89, wherein the compound VIII contains an impurity selected from a group consisting of: compound VII, compound IX and mixtures thereof.

91. The process according to claim 90, wherein the compound VII is present in an amount not greater than 0.3% area by HPLC.

92. The process according to claim 90 or 91, wherein the compound VII is present in an amount of 0.1% to 0.3% area by HPLC of compound VII.

93. The process according to any of claims 90 to 92, wherein the compound IX is present in an amount not greater than 1% area by HPLC.

9. The process according to any of claims 90 to 93, wherein the compound IX is present in an amount of 0.5% area by HPLC of compound IX.

95. A process for preparing rocuronium bromide from compound VIII comprising: (a) combining Compound VIII, a polar aprotic organic solvent, allyl bromide, and at least one inorganic base to obtain a mixture; and (b) isolating rocuronium bromide from the mixture.

95. The process according to any of claims 1 and 95, wherein the polar aprotic organic solvent is selected from the group consisting of halogenated hydrocarbon, ester and ketone.

97. The process according to claim 96, wherein the halogenated hydrocarbon is a halogenated hydrocarbon of C1-2.

98. The process according to claim 97, wherein the C1-2 halogenated hydrocarbon is dichloromethane.

99. The process according to any of claims 96 to 98, wherein the ester is ethyl acetate.

100. The process according to any of claims 96 to 98, wherein the ketone is C3-4 ketone.

101. The process according to claim 100, wherein the C3-4 ketone is acetone.

102. The process according to any of claims 1 and 95 to 96, wherein the polar aprotic organic solvent is dichloromethane.

103. The process according to any of claims 1 and 95 to 102, wherein the allyl bromide is present in an amount of 1.3 to 3 mol equivalents for each mole of compound VIII.

104. The process according to any of claims 1 and 95 to 103, wherein the mixture obtained in step (a) of claim 1, and in step (a) of claim 95, has a water content lower than 0.1% determined by Kart Fischer.

105. The process according to any of claims 1 and 95 to 104, wherein the inorganic base is selected from the group consisting of alkaline and aluminum bases.

106. The process according to claim 105, wherein the alkaline base is sodium carbonate, sodium bicarbonate or potassium carbonate.

107. The process according to claim 105 or 106, wherein the aluminum base is aluminum oxide.

108. The process according to any of claims 1 and 95 to 104, wherein the inorganic base is sodium carbonate.

109. The process according to any of claims 1 and 95 to 108, wherein the mixture in step (a) of claim 1, and in step (b) of claim 93 is stirred at a temperature of 15 ° C. at 40 ° C, before isolating Rocuronium bromide.

110. The process according to any of claims 1 and 95 to 109, wherein the mixture in step (b) is maintained for 20 hours to 24 hours, before isolating rocuronium bromide.

111. The process according to any of claims 1 and 95 to 109, wherein the Crude Roe of the formula I is purified by a process comprising: a) dissolving the crude rocuronium bromide in a polar aprotic organic solvent to form a solution; b) adding a decolorizing agent otatively combined with a base to the solution to form a first suspension; c) filter the first suspension; d) adding the filtrate to an antisolvent and stirring vigorously to obtain a second suspension;

e) recovering the wet solid of Rocuronium bromide from the second suspension; and f) drying the wet Rocuronium bromide at a temperature not higher than 35 ° C.